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Identification and characterisation of functional Kir6.1-containing ATP-sensitive potassium channels in the cardiac ventricular sarcolemmal membrane.
Brennan, Sean; Chen, Shen; Makwana, Samir; Esposito, Simona; McGuinness, Lauren R; Alnaimi, Abrar I M; Sims, Mark W; Patel, Manish; Aziz, Qadeer; Ojake, Leona; Roberts, James A; Sharma, Parveen; Lodwick, David; Tinker, Andrew; Barrett-Jolley, Richard; Dart, Caroline; Rainbow, Richard D.
Afiliación
  • Brennan S; Department of Cardiovascular and Metabolic Medicine and Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK.
  • Chen S; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  • Makwana S; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  • Esposito S; Department of Cardiovascular and Metabolic Medicine and Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK.
  • McGuinness LR; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  • Alnaimi AIM; Department of Cardiovascular and Metabolic Medicine and Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK.
  • Sims MW; Department of Cardiovascular and Metabolic Medicine and Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK.
  • Patel M; Department of Cardiac Technology, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
  • Aziz Q; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  • Ojake L; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  • Roberts JA; William Harvey Research Institute, Queen Mary University of London, London, UK.
  • Sharma P; William Harvey Research Institute, Queen Mary University of London, London, UK.
  • Lodwick D; Department of Cardiovascular and Metabolic Medicine and Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK.
  • Tinker A; Department of Cardiovascular and Metabolic Medicine and Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK.
  • Barrett-Jolley R; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  • Dart C; William Harvey Research Institute, Queen Mary University of London, London, UK.
  • Rainbow RD; Department of Musculoskeletal and Ageing Science, University of Liverpool, Liverpool, UK.
Br J Pharmacol ; 181(18): 3380-3400, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38763521
ABSTRACT
BACKGROUND AND

PURPOSE:

The canonical Kir6.2/SUR2A ventricular KATP channel is highly ATP-sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity. Pharmacological activation of KATP channels is cardioprotective, but physiologically, it is difficult to understand how these channels protect the heart if they only open under extreme metabolic stress. The presence of a second KATP channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active Kir6.1-containing KATP channel in ventricular cardiomyocytes. EXPERIMENTAL

APPROACH:

Patch-clamp recordings from rat ventricular myocytes in combination with well-defined pharmacological modulators was used to characterise these newly identified K+ channels. Action potential recording, calcium (Fluo-4) fluorescence measurements and video edge detection of contractile function were used to assess functional consequences of channel modulation. KEY

RESULTS:

Our data show a ventricular K+ conductance whose biophysical characteristics and response to pharmacological modulation were consistent with Kir6.1-containing channels. These Kir6.1-containing channels lack the ATP-sensitivity of the canonical channels and are constitutively active. CONCLUSION AND IMPLICATIONS We conclude there are two functionally distinct populations of ventricular KATP channels constitutively active Kir6.1-containing channels that play an important role in fine-tuning the action potential and Kir6.2/SUR2A channels that activate with prolonged ischaemia to impart late-stage protection against catastrophic ATP depletion. Further research is required to determine whether Kir6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sarcolema / Miocitos Cardíacos / Canales KATP / Ventrículos Cardíacos Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sarcolema / Miocitos Cardíacos / Canales KATP / Ventrículos Cardíacos Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido